Our increased understanding of the complexity of the microbiome has revealed great potential for pathogenic consequences. The effects of these interactions may be best revealed in further study of the oral cavity. The oral disease burden is exacerbated by activation of opportunistic tumorviruses resulting in oral morbidity and malignancy. Accumulating evidence suggests that epigenetic modifications are at the core of tumorviral pathogenesis modulating 1) host antiviral response and 2) viral reactivation, replication and expression of viral oncoproteins. DNA tumorviruses replicate in oral epithelia and are shed in oral fluids, inferring that replication and reactivation from latency are ongoing. A fundamental question is lack of knowledge regarding the latent to lytic transition in vivo. Why are these viruses so successful in the mouth? We suggest that certain oral bacteria act as environmental triggers that allow for oral epigenetic reprogramming. We now have compelling evidence that oral bacterial products deregulate chromatin modifying enzymes, activate histone marks H3Ac and H4Ac, modify tumorviral promoters, and enhance viral gene expression associated with reactivation and oncogenesis in a species specific manner. Further, these bacterial products diminished the HDAC-associated antiviral interferon response. Collectively, these findings led us to hypothesize that within DNA tumorvirus infected cells, oral bacterial products alter the epigenetic landscape to enhance viral replication and alter cellular innate immune responses in the oral cavity. To test this hypothesis, we will focus on the identification of epigenetic elements central to bacterial modulation of early events in tumorviral pathogenesis. The study goals are to determine: (1) how the common oral pathogen P. gingivalis facilitates viral chromatin modifications critical to reactivation and oncogene expression (SA1 in vitro) (2) modification of host chromatin and gene expression central to the antiviral response (SA2 in vitro) and (3) in vivo correlates of active tumorviral chromatin and concurrent oral bacterial infections (SA3 in vivo). We will employ both standard and modern molecular methods, such as RNA-seq and ChIP-seq, together with targeted inhibition of epigenetic cellular processes to discern the mechanisms of viral chromatin regulation in Pg treated cells. We are uniquely positioned to accomplish these studies at UNC with leading expertise in epigenetics, oral medicine, virology, bacteriology, and computational analysis.
Many Americans become immunosuppressed as a result of transplant, autoimmunity, and AIDS and are susceptible to reactivation of tumorviruses that cause up to 100% of the cancers that develop in this group. These viruses are often dormant, but actively replicate in the mouth. In order to improve treatment outcomes, we seek to understand how oral bacteria modify these viral genomes moving them to an active state and enhancing disease.
|Sanders, Anne E; Patton, Lauren L; Webster-Cyriaque, Jennifer (2015) Periodontitis and oral human papillomavirus. J Am Dent Assoc 146:715-6|
|Doolittle-Hall, Janet M; Cunningham Glasspoole, Danielle L; Seaman, William T et al. (2015) Meta-Analysis of DNA Tumor-Viral Integration Site Selection Indicates a Role for Repeats, Gene Expression and Epigenetics. Cancers (Basel) 7:2217-35|
|Doolittle, J M; Webster-Cyriaque, J (2014) Polymicrobial infection and bacterium-mediated epigenetic modification of DNA tumor viruses contribute to pathogenesis. MBio 5:e01015-14|